Dual-modality micro-invasive neural probes

Abstract

A probe for insertion into a brain tissue includes a tubular body having an inner lumen and at least two carbon fiber electrode threads (CFETs) extending through the inner lumen of the tubular body. Each CFET includes a carbon fiber having a proximal portion and a distal portion. The proximal portion of the carbon fiber is coated with a polymer. The distal portion of the carbon fiber is exposed to allow direct contact with the brain tissue. The carbon fiber of each CFET has an aspect ratio between 100 and 1500.

Description

8123-112336-02DUAL-MODALITY MICRO-INVASIVE NEURAL PROBESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 708,091, filed October 16, 2024, which is incorporated herein by reference in its entirety.FIELD

[0002] The present disclosure concerns micro-invasive neural probes and the methods of fabricating the same.ACKNOWLEDGMENT OF GOVERNMENT SUPPORT

[0003] This invention was made with government support under NS 107639 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND

[0004] Neural probes are important tools for recording electrophysiological and / or neurochemical signals in neural tissues, providing valuable insights into the functioning of neural circuits and the underlying mechanisms of behavior. Despite the recent advancements in neural probe technologies, there is still potential for improvement, particularly in developing neural probes that enable studying cellular-scale interactions between molecular and electrical neuronal signals.SUMMARY

[0005] Described herein are devices and apparatuses that can be used as micro-invasive neural probes, as well as methods and systems for fabricating the same. As described more fully below, the disclosed technologies overcome many deficiencies of conventional neural probe technologies.

[0006] According to certain aspects of the disclosure, a probe for insertion into brain tissue includes a tubular body having an inner lumen, and at least two carbon fiber electrode threads (CFETs) extending through the inner lumen of the tubular body. Each CFET includes a carbon fiber having a proximal portion and a distal portion. The proximal portion of the carbon fiber is coated with a polymer, and the distal portion of the carbon fiber is exposed to allow direct contact with the brain tissue. The carbon fiber of each CFET has an aspect ratio between 100 and 1500.

[0007] According to certain aspects of the disclosure, a method for fabricating a probe for insertion into brain tissue include: forming at least two CFETs, threading the at least two CFETs through an inner lumen of a tubular body, connecting one of the at least two CFETs to8123-112336-02 a first circuitry configured to measure electrophysiological signals of the brain tissue, and connecting another one of the at least two CFETs to a second circuitry configured to measure neurochemical signals of the brain tissue. Each CFET has a carbon fiber having an aspect ratio between 100 and 1500.

[0008] According to certain aspects of the disclosure, a probe for insertion into brain tissue include a tubular body having an inner lumen, and a plurality of CFETs extending through the inner lumen of the tubular body. Each CFET includes a carbon fiber having a proximal portion and a distal portion. The proximal portion of the carbon fiber is coated with a polymer, and the distal portion of the carbon fiber is exposed to allow direct contact with the brain tissue. The plurality of CFETs includes a first CFET and a second CFET. The distal portion of the carbon fiber of the second CFET has a larger surface area than the distal portion of the carbon fiber of the first CFET. The first CFET is electrically connected to a first circuitry configured to measure electrophysiological signals of the brain tissue surrounding the distal portion of the carbon fiber of the first CFET. The second CFET is electrically connected to a second circuitry configured to measure neurochemical signals of the brain tissue surrounding the distal portion of the carbon fiber of the second CFET.

[0009] The foregoing and other features and advantages of the disclosed technologies will become more apparent from the following detailed description, which proceeds with reference to the accompanying figures.BRIEF DESCRIPTION OF THE DRAWINGS

[0010] FIG. 1A schematically depicts a neural probe, according to one example.

[0011] FIG. IB is an enlarged view of a distal end portion of the neural probe of FIG. 1 A.

[0012] FIG. 2A is a photo of a prototype neural probe.

[0013] FIG. 2B is an enlarged view of a distal end portion of a tubular body of the neural probe of FIG. 2A.

[0014] FIG. 2C is an enlarged view of portions of carbon fibers included in the neural probe of FIG. 2A.

[0015] FIG. 3 is a block diagram illustrating example head stages that can be connected to any of the neural probes disclosed herein.

[0016] FIG. 4 is a flowchart describing an example overall method for fabricating a neural probe.

[0017] FIG. 5 is a flowchart describing an example method for forming a carbon fiber electrode thread.

[0018] FIG. 6A schematically depicts an example setup for etching a tungsten wire.8123-112336-02

[0019] FIG. 6B schematically depicts attaching a carbon fiber to a tungsten wire.

[0020] FIG. 7 A schematically depicts an example setup that can be used for polymer coating of one or more carbon fiber-tungsten wire assemblies.

[0021] FIG. 7B schematically depicts cryogenic flame etching a distal end portion of a carbon fiber, according to one example.

[0022] FIG. 8A schematically depicts inserting two carbon fiber electrode threads into a tubular body, according to one example.

[0023] FIG. 8B schematically depicts sealing both ends of the tubular body of FIG. 8A, according to one example.

[0024] FIG. 8C schematically depicts reinforcing proximal end portions of the two carbon fiber electrode threads of FIG. 8A, according to one example.

[0025] FIG. 9 is a block diagram of an example computing system which can be used in conjunction with head stages for the neural probes described herein.DETAILED DESCRIPTIONGeneral Considerations

[0026] For purposes of this description, certain aspects, advantages, and novel features of the embodiments of this disclosure are described herein. The disclosed methods, apparatus, and systems should not be construed as being limiting in any way. Instead, the present disclosure is directed toward all novel and nonobvious features and aspects of the various disclosed examples, alone and in various combinations and sub-combinations with one another. The methods, apparatus, and systems are not limited to any specific aspect or feature or combination thereof, nor do the disclosed examples require that any one or more specific advantages be present or problems be solved. The technologies from any example can be combined with the technologies described in any one or more of the other examples. In view of the many possible examples to which the principles of the disclosed technology may be applied, it should be recognized that the illustrated examples are only preferred examples and should not be taken as limiting the scope of the disclosed technology.

[0027] Although the operations of some of the disclosed examples are described in a particular, sequential order for convenient presentation, it should be understood that this manner of description encompasses rearrangement, unless a particular ordering is required by specific language set forth herein. For example, operations described sequentially may in some cases be rearranged or performed concurrently. Moreover, for the sake of simplicity, the attached figures may not show the various ways in which the disclosed methods can be used in conjunction with other methods. Additionally, the description sometimes uses terms8123-112336-02 like “provide” or “achieve” to describe the disclosed methods. These terms are high-level abstractions of the actual operations that are performed. The actual operations that correspond to these terms may vary depending on the particular implementation and are readily discernible by one of ordinary skill in the art. Any theories of operation are to facilitate explanation, but the disclosed systems, methods, and apparatus are not limited to such theories of operation.

[0028] As used in this application and in the claims, the singular forms “a,” “an,” and “the” include the plural forms unless the context clearly dictates otherwise. As used herein, “and / or” means “and” or “or,” as well as “and” and “or.” Additionally, the term “includes” means “comprises.” Further, the terms “coupled” and “connected” generally mean electrically, electromagnetically, and / or physically (e.g., mechanically or chemically) coupled or linked and does not exclude the presence of intermediate elements between the coupled or associated items absent specific contrary language.

[0029] As used herein, the term “proximal” refers to a position, direction, or portion of a device that is closer to the user and further away from the probe insertion site. As used herein, the term “distal” refers to a position, direction, or portion of a device that is further away from the user and closer to the probe insertion site. The terms “longitudinal” and “axial” refer to an axis extending in the proximal and distal directions, unless otherwise expressly defined.

[0030] Directions and other relative references (e.g., inner, outer, upper, lower, top, bottom, etc.) may be used to facilitate discussion of the drawings and principles herein, but are not intended to be limiting. For example, certain terms may be used such as “inside,” “outside,” “interior,” “exterior,” and the like. Such terms are used, where applicable, to provide some clarity of description when dealing with relative relationships, particularly with respect to the illustrated examples. Such terms are not, however, intended to imply absolute relationships, positions, and / or orientations. For example, with respect to an object, an “upper” part can become a “lower” part simply by turning the object over. Nevertheless, it is still the same part and the object remains the same.

[0031] In any of the examples described herein, unless specified otherwise, a value’s range (e.g., from a first end point to a second end point, or between a first end point and a second endpoint) is inclusive of the specified end points.

[0032] In any of the examples described herein, unless specified otherwise, the terms “approximately” and “about” mean that the listed value and any value that is within 20% of8123-112336-02 the listed value. For example, “about 10 mm” means any value between about 8 mm and about 12 mm, inclusive.Overview of Neural Probes for Deep Brain Structures

[0033] Neural probes for deep brain structures have revolutionized our understanding of brain activity, particularly in relation to neural circuits and neurochemical dynamics. These tools enable researchers to measure electrical and chemical signals from neurons within complex and deeply embedded brain regions. Neural recording technologies, such as multielectrode arrays and microelectrodes, have paved the way for exploring brain structures like the basal ganglia and hippocampus, which are associated with neural functions such as memory, learning, and motor control. Techniques have also been developed for deep brain stimulation (DBS) using neural probes. However, despite significant advancements, there are still notable technical challenges in the state-of-the-art approaches, particularly when probing deep brain structures in larger animals such as non-human primates or humans.

[0034] One major challenge in neural recording is the precise targeting of deep brain structures. As the brain’s internal architecture is highly complex, it is important to deploy probes that can reliably and accurately reach targeted regions without causing undue damage to surrounding tissue. The targeting of such structures requires probes that are both physically capable of reaching deep regions and sensitive enough to detect the low-amplitude signals generated by individual neurons or local groups of neurons. Probes designed for rodents, for instance, may not be suitable for non-human primates such as Rhesus monkeys, where deep brain structures like the striatum or thalamus are located more than 15 to 35 mm below the cortical surface. These probes are even more inadequate to reach the deep brain structure in humans, which can be located up to 90 mm below the cortical surface. This depth poses significant limitations to probe durability and functionality, as the longer lengths required for deep brain insertion increase the risk of buckling or breakage. Similar challenges arise in using probes for DBS in non-human primates and / or humans.

[0035] Another technical challenge is the ability to record both electrical and neurochemical signals simultaneously from the same region. Understanding how neurotransmitters, such as dopamine, interact with neural circuits during behavior can help unravel the complexities of brain function. Dopamine plays an important role in learning, motivation, and neuroplasticity, but current technologies are often unable to capture the real-time interaction between dopamine release and neuronal spiking in awake, behaving subjects. This gap in technology is particularly significant in non-human primates and / or humans, where the ability to monitor both types of signals in close proximity is important for studying naturalistic8123-112336-02 behaviors. This challenge is compounded when both recording signals from a deep brain structure and stimulating the same region.

[0036] Spatial heterogeneity in neural signals presents additional difficulties. Neurochemical and electrophysiological activities can vary widely across different brain regions, even within localized areas of the same structure. In the striatum, for example, dopamine release has been observed to occur across different spatial scales, ranging from focal, micrometer- sc ale domains to broader, millimeter-scale waves. This variability in spatial dynamics makes it challenging to design probes that can capture neural activity across such diverse scales while still maintaining high spatial resolution. Current techniques, such as wide-field imaging with fluorescent reporters, offer some insights into the spatial distribution of dopamine, but these tools often lack the resolution required to simultaneously track both electrical activity and neurochemical changes in a highly localized manner.

[0037] Additionally, chronic recording in non-human primates and / or humans poses specific obstacles, especially when aiming for long-term studies of neural dynamics over days, weeks, or months. While advances in micro-invasive sensors, such as carbon fiber-based electrodes, have allowed for stable, long-term recordings in rodent models, translating these technologies to non-human primates and / or humans remains a major hurdle. The larger brain volumes and deeper structures in primates require more durable, flexible, and biocompatible materials that can maintain their functionality over extended periods without causing inflammation or signal degradation. Ensuring that these sensors can withstand the mechanical stress of prolonged brain implantation is important to achieving consistent and reliable data collection. Similar challenges exist for chronic DBS in non-human primates and / or humans, where probes must remain functional and biocompatible over extended periods to avoid tissue damage and maintain therapeutic efficacy.

[0038] The scalability of current neural recording platforms also remains limited. State-of- the-art probes support a dense electrode array for multi-channel recording. However, these systems are optimized primarily for electrical recordings and do not yet fully address the need for integrated neurochemical measurements, particularly in species like non-human primates or humans, where combined electrical and chemical sensing is important for understanding complex brain functions. While there are ongoing efforts to develop multi-modal probes capable of measuring both types of signals, the current generation of tools remains suboptimal for non-human primate and / or human use, particularly in terms of sensor placement and signal sensitivity. Moreover, a multi-channel DBS system capable of both recording and stimulating across multiple regions simultaneously is still lacking.8123-112336-02

[0039] Furthermore, recording the dynamic interactions between neural signals and behavior introduces another layer of complexity. Linking cellular-level neuronal activity with high- level behaviors, such as decision-making or learning, requires not only precise spatial and temporal resolution but also the ability to record from multiple brain regions simultaneously. The interconnected nature of brain networks means that activity in one region, such as the prefrontal cortex, may influence and be influenced by deep structures like the basal ganglia. Thus, comprehensive neural recording systems must be able to capture this multi-regional activity in a coordinated manner to fully understand how different brain regions interact during complex behaviors.

[0040] The technologies described herein address many of the challenges described above. Specifically, the disclosed neural probes enable simultaneous recording of both electrophysiological and neurochemical signals within brain tissue, including in deep brain structures such as the striatum, thalamus, and basal ganglia. These advanced probes are designed not only for short-term applications, but also for long-term use, allowing for stable, chronic recordings over extended periods. Additionally, the probes can be inserted into multiple brain regions, making them versatile tools for studying neural circuits across various interconnected areas. The disclosed neural probes are adaptable for use in a range of species, including non-human primates, humans, and other animals, offering broad applicability in neuroscientific research and clinical applications. Although the following embodiments use the brain tissue as an example target for probe insertion, it should be understood that the disclosed neural probes are also suitable for targeting other organs, such as the spinal cord and gastrointestinal tract. Furthermore, the disclosed neural probes can be configured to deliver electrical stimulation to target tissues, providing a multifunctional platform for both monitoring and closed-loop therapeutic interventions.

[0041] Exemplary applications of the disclosed neural probes include, but are not limited to, use as feedback sensors in closed-loop deep brain stimulation systems, where real-time neurochemical biomarkers (e.g., dopamine) can be monitored to guide therapy for conditions such as Parkinson’s disease, mood disorders, and addiction. The disclosed neural probes may also be employed during stereotactic gene therapy procedures, for example in a peri-infusion or chronic monitoring context, to provide localized, real-time confirmation of on-target delivery and functional impact. In addition, the neural probes disclosed herein can support objective monitoring of neurotransmitter fluctuations during substance withdrawal, thereby informing dosing regimens. The neural probes may further be used in acute diagnostic8123-112336-02 settings to assist with targeting or confirming the placement of invasive interventions, including, but not limited to, deep brain stimulation implantation.Exemplary Probe Structure

[0042] FIGS. 1 A-1B schematically depict (not drawn to scale) a neural probe 100 (or simply “probe”) that can be inserted into brain tissue, according to one example.

[0043] In the depicted example, the probe 100 includes a tubular body 102 having an inner lumen 104, and two carbon fiber electrode threads (CFETs) 110A, HOB (collectively, 110) extending through the inner lumen 104 of the tubular body 102. In other examples, there can be more than two (e.g., three, four, five, six, seven, eight, or more) CFETs extending through the inner lumen of the tubular body.

[0044] The probe 100 is configured to be sufficiently rigid to ensure precise insertion and accurate targeting several centimeters deep into the brain tissue. In some examples, the tubular body 102 can be a glass tube composed of a mixture of silicon dioxide (i.e., silica) with other oxides like sodium oxide and calcium oxide. In some examples, the tubular body 102 can be a fused silica tube composed of high-purity silicon dioxide (e.g., with purity level of silica of at least 99%, or higher than 99.9%). Fused silica tubes generally have higher tensile strength than regular glass tubes.

[0045] As shown in FIGS. 1 A-1B, the two CFETs 110 extend out of a distal end portion 106 of the tubular body 102. In some examples, the two CFETs 110 also extend out of a proximal end portion 108 of the tubular body 102. The proximal ends of the two CFETs 110 can be respectively connected to conducting wires 112, which are further connected to respective head stages, as described further below.

[0046] Each CFET 110 includes a carbon fiber 114 (respectively denoted as 114A and 114B in FIG. IB) and a threading wire 116 (respectively denoted as 116A and 116B in FIG. IB). The use of carbon fibers in CFETs provides an optimal interface for sensitive neurochemical recording (e.g., dopamine detection) and electrophysiological recording (e.g., measuring local field potentials and / or neuronal spike activity).

[0047] In some examples, the carbon fibers 114 substantially extend out of the distal end portion 106 of the tubular body. In some examples, the distal end portion 106 of the tubular body has a tapered shape. For example, FIG. IB shows that the distal end portion 106 tapers radially inwardly in a distal direction. When inserting the probe 100 into the brain tissue, this tapered design can decrease insertion force (thus minimizing tissue damage) and reduce deflection of the tubular body (thus improving insertion precision). Additionally, the tapered8123-112336-02 distal end portion 106 also makes it easier to thread CFETs 110 into the tubular body 102, as described further below.

[0048] The threading wires 116 substantially extend through and enclosed by the inner lumen 104 of the tubular body. In some examples, the threading wires 116 comprise tungsten (W), thus they can also be referred to as tungsten wires. In some examples, the threading wires 116 can comprise other metals or alloys so long as they are conductive and have sufficiently high tensile strength. The threading wires 116 can be connected to the respective carbon fibers 114 via conductive epoxy so that voltage and / or current signals picked up by the carbon fibers 114 can be conducted to corresponding head stages via the threading wires 116.

[0049] Each carbon fiber 114 has a proximal portion 118 and a distal portion 120. The proximal portion 118 of the carbon fiber is covered by a coated layer 126. For example, the coated layer 126 can be formed by coating the proximal portion 118 with a polymer which provides electrical insulation for the carbon fiber. In some examples, the polymer of the coated layer can be parylene. In one specific example, the polymer can be parylene C. Thus, the proximal portion 118 of the carbon fiber can also be referred to as parylene-coated carbon fiber. The distal portion 120 of the carbon fiber can be exposed to allow direct contact with the brain tissue when the probe 100 is inserted therein. Thus, the distal portion 120 of the carbon fiber can also be referred to as exposed carbon fiber.

[0050] For each CFET 110, a body portion of the threading wire 116 (i.e., the portion of the threading wire that is situated within the inner lumen 104 and covered by the tubular body 102) is also coated with a polymer (e.g., parylene or the like). This polymer coating provides electrical insulation for the threading wires 116 of the two CFETs, ensuring that the signals conducted along each threading wire remain isolated from one another. Additionally, the polymer coating can facilitate the insertion of the two CFETs 110 through the inner lumen 104 during the fabrication of the probe 100, as described further below. For example, the polymer coating provides a smooth surface which can reduce friction, thereby allowing for easier threading of the CFETs 110 through the inner lumen 104.

[0051] As examples, FIGS. 2A-2C depict a prototype neural probe 200 that can be used for inserting into brain tissue. The probe 200 has a similar structure as the probe 100. For example, the probe 200 has a tubular body 202 and two CFETs 210A, 210B (collectively, 210) extending through an inner lumen 204 of the tubular body 202. Each CFET 210 includes a carbon fiber 214 extending out of a distal end portion 206 (having a tapered shape) of the tubular body 202 and a threading wire 216 (e.g., tungsten wire) substantially enclosed within the inner lumen 204 of the tubular body 202. Each carbon fiber 214 has an insulated8123-112336-02 proximal portion 218 with parylene coating and an exposed distal portion 220 without parylene coating.Exemplary Probe Modalities

[0052] The exposed distal portion (e.g., 120, 220) of the carbon fiber can act as an electrode. In some examples, the electrode can be configured as a sensing electrode for measuring neurochemical and / or electrophysiological signals of the surrounding brain tissue. In other examples, the electrode can be configured as a pacing electrode to deliver electrical pulses to the surrounding brain tissue (e.g., for DBS).

[0053] Configuration of the electrodes in a probe can be implemented by selectively connecting the CFETs of the probe to various head stages. As described more fully below, the head stages (e.g., to which the conducting wires 112 are connected) can include specific circuits and / or data processing units configured to measure, process, and / or record signals detected by the electrodes, and / or deliver electrical pulses to the electrodes.

[0054] Any of the neural probes described herein (e.g., 100, 200) can be multi-modal. For instance, the probe 100 of FIGS. 1A-1B can be configured to have dual modalities by configuring the electrodes of the two CFETs 110 differently. In one example, one CFET (e.g., 110A) can be connected to a head stage configured to measure electrophysiological signals around the distal portion 120 of its corresponding carbon fiber (e.g., 114A), while another CFET (e.g., HOB) can be connected to another head stage configured to measure neurochemical signals around the distal portion 120 of its corresponding carbon fiber (e.g., 114B). As another example, one CFET can be configured as a sensing electrode (e.g., to measure electrophysiological and / or neurochemical signals in the surrounding brain tissue), while the other CFET can be configured as a pacing electrode to deliver electrical pulses to the surrounding brain tissue. In yet another example, the electrode of one CFET can be configured as both a sensing electrode and a pacing electrode by employing switching head stages (e.g., via external commands and / or programmed software) that alternates between sensing and pacing modes.

[0055] More sophisticated combination of modalities can be achieved when the probe has more than two CFETs. For example, in a tri-modal configuration, one CFET can be dedicated to measuring electrophysiological signals, a second CFET can be dedicated to measuring neurochemical signals, and a third CFET can be configured as a pacing electrode to deliver electrical stimulation to the surrounding brain tissue.8123-112336-02Exemplary Dimensions of Neural Probes

[0056] The neural probes disclosed herein are configured to be sufficiently rigid and long to penetrate and reach deep brain structures. Despite their rigidity, these probes are configured to be micro-invasive such that the target brain tissue is minimally perturbed and virtually scar-free. Specifically, these probes can be fabricated in specific dimensions that are critical to reduce trauma or injury when inserting them into the brain tissue. Some representative dimension parameters of the probes are described below with reference to FIGS. 1A-1B, using the probe 100 as an example.

[0057] The tubular body 102 has an axial length (LI) that is configured to allow inserting the probe into deep brain structures of non-human primates or humans. In some examples, LI is between 5 and 100 centimeters, or between 8 and 80 centimeters. For non-human primates, LI can be between 8 and 12 centimeters (e.g., about 9 centimeters). For humans, LI can be between 25 and 50 centimeters (e.g., about 45 centimeters). In practice, depending on the specific application and / or anatomical considerations, the full length of the tubular body 102 may not be inserted into the brain, depending on the specific application and anatomical requirements.

[0058] The tubular body 102 has an outer diameter (D2) that is sufficiently small to reduce tissue injury or inflammation when inserting the probe into the brain tissue. Specifically, D2 is configured such that any tissue injury or inflammation, if indeed induced by the probe penetration, would not negatively impede sensor measurements or affect the accuracy of the recorded signals. In some examples, D2 is between 50 and 1000 microns, or between 100 and 200 microns, or between 150 and 180 microns. In one specific example, D2 is about 165 microns.

[0059] As described above, the distal end portion 106 of the tubular body can have a tapered shape to further reduce tissue injury or inflammation when inserting the probe into the brain tissue. The distal end portion 106 can feature a tapered cut with a cut angle (relative to a longitudinal axis of the tubular body) of between 30 and 60 degrees, or in one specific example, approximately 45 degrees.

[0060] The inner lumen 104 of the tubular body has a diameter (DI) that is limited by the outer diameter (D2) of the tubular body. The difference between DI and D2 defines a thickness of the tubular body which is configured to ensure a sufficient rigidity of the tubular body. Additionally, DI is configured to allow two or more CFETs to thread therethrough. For example, when D2 is between 50 and 1000 microns, DI can be between 20 and 500 microns. As another example, when D2 is between 150 and 180 microns, DI can be between8123-112336-0280 and 120 microns, or between 90 and 110 microns. In one specific example, DI is about 100 microns.

[0061] The body portion of the threading wire 116, including the polymer coating, has an outer diameter (D3) that is sufficiently small so that two or more threading wires 116 can be inserted through the inner lumen 104. Meanwhile, D3 is configured to be large enough to provide a sufficient tensile strength of the CFETs so that they do not buckle or tangle together when threading them through the small inner lumen 104 (e.g., having a sub-millimeter diameter). In some examples, D3 is between 10 and 50 microns, or between 20 and 40 microns. In one specific example, D3 is about 30 microns.

[0062] The carbon fiber 114 of each CFET, without polymer coating (e.g., the distal portion 120), has an outer diameter that is between 2 and 10 microns, or between 4 and 8 microns. In one specific example, the carbon fiber (uncoated) has an outer diameter of 7 microns. In another specific example, the carbon fiber (uncoated) has an outer diameter of 5 microns.

[0063] The thickness of the polymer coating around the carbon fiber is configured to provide sufficient insulation of the carbon fiber, and in some circumstances, increase the tensile strength of the carbon fiber. In some examples, the carbon fiber with polymer coating (e.g., the proximal portion 118) can have an outer diameter that is between 1 and 20 microns. Depending on the thickness of the polymer coating, the outer diameter of the polymer-coated carbon fiber can be between 0.1 and 10 microns larger than the outer diameter of the uncoated carbon fiber. In some examples, the outer diameter of the polymer-coated carbon fiber can be between 0.5 and 5 microns, or between 1 and 3 microns, larger than the outer diameter of the uncoated carbon fiber. In one specific example, when the uncoated carbon fiber (e.g., the distal portion 120) has an outer diameter of about 7 microns, the polymer coated carbon fiber (e.g., the proximal portion 118) has an outer diameter of about 10 microns.

[0064] As described above, the carbon fiber 114 of each CFET substantially extends out of the distal end portion 106 of the tubular body. An axial length (L2) of a carbon fiber extending outside the tubular body, measured between a tip or distal end 122 (e.g., the tip) of the carbon fiber 114 and a tip or distal end 124 of the tubular body 102, is configured to be in a predefined range. On one hand, L2 is configured to be large enough so that the electrode (e.g., the exposed distal portion 120) is spaced sufficiently apart from the tip or distal end 124 of the tubular body to reduce or minimize the likelihood of picking up injury current around the distal end 124 due to probe penetration of the brain tissue. On the other hand, L2 should not be too long to avoid buckling or bending (especially considering the hair-thin carbon fiber8123-112336-02 has a diameter of only a few microns) when inserting the probe into the brain tissue. In some examples, the range of L2 is between 0.5 and 25 millimeters, or between 1 and 20 millimeters. In one specific example, L2 of a carbon fiber can be about 5 mm. In another specific example, L2 of a carbon fiber can be about 10 mm.

[0065] As described above, the carbon fiber 114 of each CFET can be connected to a threading wire 116 threading through the inner lumen 104. A proximal end portion 128 of the carbon fiber 114 (e.g., an end segment of the proximal portion 118) that is coupled to the threading wire 116 can be inside (and covered by) the tubular body 102. In some examples, the proximal end portion 128 of the carbon fiber that is inside the tubular body can have an axial length that is between 0.1 and 10 mm, or between 0.2 and 5 mm. In one specific example, the axial length of the proximal end portion of the carbon fiber that is inside the tubular body can be about 1 mm.

[0066] The carbon fibers 114 of the CFETs have large aspect ratios due to their small diameters (e.g., several microns) and relatively long total axial length (e.g., a few or over ten millimeters). As described herein, the aspect ratio of each carbon fiber 114 is defined as the ratio of its total length — including both the polymer-coated proximal portion 118 and the uncoated distal portion 120 — to the diameter of the polymer-coated proximal portion 118. In some examples, the aspect ratio of a carbon fiber in each CFET is between 50 and 4000, or between 80 and 2000, or between 100 and 1500. For example, when the polymer-coated carbon fiber has a diameter of 10 microns and the total length of the carbon fiber is about 15 millimeters, its aspect ratio is about 1500.

[0067] As described above, the distal portion 120 of the carbon fiber can be used as an electrode interfacing the brain tissue. In some examples, an axial length (L3) of the distal portion 120 can vary based on the configuration of the electrode. For instance, when the electrode is configured to measure electrophysiological signals of the surrounding brain tissue, L3 can be in a range between 5 and 300 microns, or between 5 and 100 microns. On the other hand, when the electrode is configured to measure neurochemical signals (e.g., signals indicating changes in dopamine concentration), L3 can be in a relatively longer range, e.g., between 100 and 300 microns or between 100 and 500 microns, to achieve a desired sensitivity of measurement. As another example, when the electrode is configured to deliver pacing pulses, L3 can be in a range between 1 micron and 6 millimeters, or between 5 microns and 5 millimeters.

[0068] In some examples, instead of, and / or in lieu of, varying the length of the distal portion 120 to achieve desired electrode performance, surface treatments can be applied to the distal8123-112336-02 portion 120 to enhance its functionality. For instance, coating the distal portion 120 with PEDOT (poly(3,4-ethylenedioxy thiophene)) or other conductive polymers can increase its surface roughness, thereby increasing the effective surface area without altering the axial length (L3). This allows for L3 to remain relatively small (e.g., between 1 and 5 microns for measuring electrophysiological signals, etc.), while still providing a sufficiently large surface area to improve signal sensitivity and reduce impedance. Other non-coating methods, such as laser etching, can also be used to increase the effective surface area of the electrodes. In some examples, regardless of their axial length (L3), the electrodes or distal portions 120 of the two carbon fibers can have different surface areas. A distal portion with a smaller surface area can be configured to measure electrophysiological signal of the surrounding brain tissue, whereas another distal portion with a larger surface area can be configured to measure neurochemical signal of the surrounding brain tissue.

[0069] The electrodes or distal portions 120 of the two carbon fibers 114, despite their lateral proximity, are configured to be axially spaced apart from one another to avoid contacting each other that would cause shorting between the electrodes. On the other hand, in some circumstances, the electrodes or distal portions 120 of the two carbon fibers 114 are desirably in close proximity so that the two electrodes can be employed to simultaneously measure, respectively, electrophysiological signals and neurochemical signals within a focal vicinity of the brain tissue. For instance, in FIG. IB, the electrode on one carbon fiber 114A can be used to measure electrophysiological signals and the electrode on the other carbon fiber 114B can be used to measure neurochemical signals, or vice versa. Simultaneous measurement within such a focal vicinity allows direct observation of the interactions between molecular and electrical neuronal signals, which can be important for understanding synaptic plasticity and adaptive behaviors within the brain tissue.

[0070] An axial distance (L4) between the tips or distal ends 122 of the two carbon fibers 114, also referred to as “pitch” hereinafter, can be used to characterize the axial spacing between the two electrodes of the probe 100. The pitch defines the spatial extent of the focal vicinity in which simultaneous measurements of neurochemical and electrophysiological signals occur. In some examples, the pitch L4 can range between 10 microns and 2 millimeters, or between 10 microns and 1 millimeter. In some examples, the pitch L4 can be smaller than 10 microns (e.g., between 1 and 10 microns) so long as the distal portions 120 of the two carbon fibers do not axially overlap with one another.8123-112336-02Example Functional Coatings

[0071] In some examples, the distal portion 120 of the carbon fiber can be further modified with one or more functional coatings to enhance sensitivity and / or expand the modality of chemical detection. Such functional coatings may include enzymes that selectively react with targeted neurotransmitters (e.g., glutamate oxidase for glutamate detection, GABA oxidase for y-aminobutyric acid (GABA) detection, etc.), thereby enabling the neural probe to transduce the presence of these molecules into measurable electrochemical signals. In some examples, aptamer-based coatings or other molecular recognition elements may be employed to provide selective binding and detection of particular neurochemicals, peptides, or other analytes of interest. These functional coatings can be used alone or in combination with conductive polymers (e.g., PEDOT) or nanostructured materials to improve effective surface area, signal-to-noise ratio, and overall recording performance. Incorporating such functional coatings enables the disclosed neural probes not only to record catecholamines such as dopamine, but also to sense a broader range of neurotransmitters and neuromodulators, thereby further supporting multimodal interrogation of neural activity.Exemplary Head Stages for Neural Probes

[0072] FIG. 3 is a block diagram depicting an instrument or interface platform 300 which includes a plurality of head stages that can be connected to any of the neural probes disclosed herein. In some examples, one or more head stages connected to a neural probe can be deemed as parts of the neural probe.

[0073] As described herein, a head stage refers to an electronic module that interfaces with the electrodes (e.g., the distal portions 120, 220) of a neural probe (e.g., via the conducting wires 112 of FIG. 1 A). In some examples, a head stage can provide signal amplification, filtering, and data acquisition (e.g., including sampling and analog-to-digital conversion) for the recorded signals. In some examples, a head stage may also include circuitry for delivering electrical stimulation pulses to specific electrodes of the probe. In some examples, multiple head stages can be independently configured to handle electrophysiological signal measurements, neurochemical signal measurements, and / or electrical stimulation, depending on the configuration of the connected probe. The interface platform 300 may also include, or in communication with, a computing system that coordinates the activities of the head stages, processes incoming signals, and transmits the data to an external device for further analysis and storage. An example computing system 900 is shown in FIG. 9 and described further below.8123-112336-02

[0074] In a non-limiting example, FIG. 3 shows that the interface platform 300 includes a first head stage 310, a second head stage 320, and a third head stage 330. The first head stage 310 can include a circuitry configured to measure electrophysiological signals of the brain tissue from a connected electrode of the neural probe. The second head stage 320 can include a circuitry configured to measure neurochemical signals of the brain tissue from another connected electrode of the neural probe. The third head stage 330 can include a circuitry configured to generate electrical pulses to yet another connected electrode of the neural probe.

[0075] As shown in FIG. 3, the first head stage 310 can be a voltage- follower head stage including an amplifier 312 with high input impedance. Local field potentials and / or neuronal spike activities picked up by an electrode of the probe can be fed to an input end 314 of the amplifier 312 for amplification and signal conditioning.

[0076] The second head stage 320 can include a current-to-voltage converter 322 that allows recording electrochemical current during simultaneous application of a control signal to induce reduction and oxidation (redox) reaction of targeted electroactive chemicals (e.g., dopamine), as used in fast-scan cyclic voltammetry (FSCV). For instance, electrochemical current detected by an electrode of the probe can be provided to one input end 324 of the current-to-voltage converter 322, while a control signal can be applied to another input end 326 of the current-to-voltage converter 322. The control signal can be programmed (e.g., by the computing system 900) and generated by a signal generator. For instance, for detecting dopamine or other catecholamines, the control signal can be a triangular voltage waveform ramping from -0.4 V to 1.3 V at a scan rate of 400 V / s, and such waveform can be applied at a rate of 10 Hz and held at -0.4V between scans. The reduction and oxidation (redox) process can lead to current changes indicative of dopamine oxidation at approximately 0.6 V (where dopamine is converted to dopamine-o-quinone) and dopamine reduction near -0.2 V (where dopamine-o-quinone is converted back to dopamine). These current changes are proportional to the concentration of dopamine in the vicinity of the electrode. By using background-subtracted voltammograms and applying techniques like principal component analysis, the measured current signals can be distinguished from other interfering molecular signals, allowing for accurate estimation of change in dopamine concentration. In some examples, alternative electrochemical recording techniques may be employed in addition to or in lieu of FSCV. For example, fast-scan controlled adsorption voltammetry (FSCAV) and square-wave voltammetry (SWV) can be utilized to quantify “tonic” or absolute8123-112336-02 concentrations of dopamine or other analytes, complementing the detection of transient or phasic fluctuations obtained with FSCV.

[0077] The third head stage 330 can be configured to generate electrical pulses for neural stimulation. For instance, the third head stage can include a pulse generator 332 that delivers controlled electrical stimuli through an electrode of the neural probe. These pulses can be programmed to modulate neural activity in the surrounding brain tissue, enabling precise intervention in neural circuits. In some examples, the pulse generator 332 can be programmed to control various parameters such as pulse shape, pulse width, and pulse frequency to tailor the stimulation to specific experimental or therapeutic needs. For example, rectangular or biphasic pulse shapes can be used, with pulse widths ranging from microseconds to milliseconds, and frequencies from a few Hertz to several hundred Hertz. These parameters can be adjusted dynamically by the computing system 900 to achieve the desired neural response and optimize the effectiveness of stimulation.Example Overall Method for Fabricating Neural Probes

[0078] FIG. 4 is a flowchart describing an example overall method 400 for fabricating a neural probe.

[0079] At step 410, at least two CFETs (e.g., the CFETs 110 of FIGS. 1A-1B) can be formed. In some aspects, each CFET includes a carbon fiber having an aspect ratio between 100 and 1500.

[0080] At step 420, the at least two CFETs can be threaded through an inner lumen of a tubular body (e.g., the inner lumen 104 of the tubular body 102 of FIGS. 1 A-1B).

[0081] At step 430, one of the at least two CFETs can be connected to a first circuitry (e.g., the first head stage 310 of FIG. 3) configured to measure electrophysiological signals of the brain tissue.

[0082] At step 440, another one of the at least two CFETs can be connected to a second circuitry (e.g., the second head stage 320 of FIG. 3) configured to measure neurochemical signals of the brain tissue.Example Method for Forming CFETs

[0083] FIG. 5 is a flowchart describing an example method 500 for forming a CFET that can be included in any of neural probes described herein. The method 500 can be used to form the at least two CFETs described at step 410 of FIG. 4. In this example, a tungsten wire is used as a threading wire (e.g., the threading wire 116). In other examples, the threading wire can be made of other types of conductive metal or alloy.

[0084] At step 510, a tungsten wire is etched to a desired radial dimension.8123-112336-02

[0085] At step 520, a carbon fiber (e.g., the carbon fiber 114) is connected to the tungsten wire to form a carbon fiber-tungsten wire assembly.

[0086] At step 530, the carbon fiber-tungsten wire assembly can be coated with a polymer, such as parylene.

[0087] At step 540, a distal end portion of the carbon fiber-tungsten wire assembly can be etched to remove the parylene coating at the distal end portion and expose the bare carbon fiber thereof.Additional Operations for Fabricating Neural Probes

[0088] Additional details for forming the CFETs and other aspects of fabricating the neural probes are described more fully below in reference to FIGS. 6A-6B, 7A-7B, and 8A-8C. It should be understood that the specific parameters, materials, and steps described below are non-limiting, and alternative configurations or methods may be utilized to achieve similar outcomes. Variations in material properties, dimensions, and fabrication techniques can be adapted to meet specific application requirements or to enhance the performance of the neural probes in various experimental and / or clinical settings.

[0089] FIG. 6A depicts an example setup for etching a tungsten wire 604. The tungsten wire 604, initially measuring approximately 10 centimeters in length and about 50 microns in diameter, can be etched down to a desired thickness, e.g., between about 20 and 30 microns. This process can include creating a slight taper on one end of the tungsten wire, where the carbon fiber will be attached, to facilitate a smooth transition from the tungsten wire 604 to the carbon fiber. In some examples, the taper extends over a length between about 2 and 3 centimeters. In some examples, the etching process can be conducted using a IM sodium hydroxide solution 602 contained in a dip coater system 600, which allows for the controlled elevation (e.g., at a predetermined rate) of the tungsten wire 604 from the solution 602 during etching. In some examples, a 15 V peak-to-peak 1 kHz electrical sinusoidal wave can be applied across the tungsten wire 604 and a reference stainless steel wire 606 to induce electrochemical etching when the tungsten wire 604 reaches its deepest level.

[0090] As shown in FIG. 6B, a carbon fiber 610 of a desired diameter (e.g., between about 5 and 7 microns) and an overall length between 25 and 30 millimeters can be attached to the tapered end portion 608 of the tungsten wire 604, e.g., using silver epoxy diluted with isopropyl alcohol (IP A), to form a carbon fiber-tungsten wire assembly 620. As described herein, the carbon fiber-tungsten wire assembly 620 can also be referred to as a CFET (similar to the CFETs 110, 210). In some examples, the overlap length of the carbon fiber 610 over the tungsten wire 604 can be between 10 and 20 millimeters (e.g., about 158123-112336-02 millimeters). This overlap can be constrained to just the tapered end portion 608 to avoid widening the overall diameter of the resulting carbon fiber-tungsten wire assembly 620, which would otherwise make it more difficult to fit into the tubular body described further below. After application, the silver epoxy can be cured (e.g., in an oven at about 80°C for about 3 hours) to ensure a strong bond between the carbon fiber 610 and tungsten wire 604.

[0091] The formed carbon fiber-tungsten wire assemblies (or CFETs) can then be coated with a polymer, such as parylene-C, using a vapor deposition process to provide electrical insulation. As illustrated in FIG. 7A, one or more carbon fiber-tungsten wire assemblies 730 (two are shown in FIG. 7A) can be placed in a rig 700. Each carbon fiber-tungsten wire assembly 730 includes a tungsten wire 704 connected to a carbon fiber 710, as described above. The parylene can be vaporized in a vacuum deposition chamber 708 of the rig, where it condenses onto the surface of the assemblies, forming a thin, conformal coating that provides electrical insulation.

[0092] To prevent the carbon fibers 710 from sticking to each other and other objects due to electrostatic and other physical interactions (which can be particularly challenging due to their significant aspect ratios), the rig 700 can be equipped with a separating mechanism, such as spatially isolated apertures 702. These apertures 702 are configured to receive and hold the carbon fibers 710, keeping them separate from one another and free-floating to ensure uniform deposition of parylene over the carbon fibers 710. Since the tungsten wires 704 are very long, the rig 700 also ensures that the tungsten wires 704 remain mostly free- floating while providing radial boundaries to prevent contact between them due to air movement and electrostatic interactions. Temporary anchoring mechanisms, such as tapes 712, can be used to affix each tungsten wire 704 to the adjacent walls of the rig 700, further preventing entanglement during the coating process.

[0093] In some examples, a liquid adhesion promoter (e.g., a mixture of 0.5 mL 3- (trimethoxysilyl)propyl methacrylate, 2.5 mL deionized water, and 500 mL IP A, stirred at about 400 rpm for about 12 hours) can be used to enhance the adhesion of parylene onto the carbon fiber-tungsten wire assemblies 730. This adhesion promoter can be applied before the parylene deposition process to ensure strong bonding between the parylene and the assemblies. In some examples, for each parylene deposition run, approximately 9 mL of this adhesion promoter can be used to coat a batch of 20 carbon fiber-tungsten wire assemblies 730. In some examples, the adhesion promoter can be placed in a container 706 with a wide opening to expedite its evaporation in the vacuum deposition chamber 708, ensuring complete evaporation of the adhesion promoter before the parylene is deposited.8123-112336-02

[0094] Once parylene coated, the parylene on a distal portion of each carbon fiber can be individually etched to expose the underlying carbon fiber to serve as the recording (or pacing) electrode. Various etching techniques can be used, such as reactive ion etching (RIE), plasma etching, laser etching, flame etching, etc. In some examples, a freeze-assist flame etching process (which can also be referred to as “cryogenic flame etching” hereinafter) can be used, as illustrated in FIG. 7B.

[0095] In some examples, each parylene-coated carbon fiber-tungsten wire assembly 730 can be placed on a temperature resistant plate 760 (e.g., a ceramic plate) with the distal portion 720 of the carbon fiber 710 hanging off the plate 760. The length of the distal portion 720 extending outside the plate 760 can be adjusted according to the desired length of the resulting electrode. In a non- limiting example, the distal portion 720 hanging off the plate 760 can have a length between 200 and 300 microns.

[0096] A portion of the carbon fiber-tungsten wire assembly 730 on the plate 760, including a proximal portion 718 of the carbon fiber 710 and a distal portion of the tungsten wire 704, can be temporarily affixed in place using ice 750 (e.g., by pouring deionized water onto the plate 760 and freezing it using dry ice). A flame torch 740 can be used to etch the distal portion 720 of the carbon fiber hanging off the plate 760. In some examples, this flaming process can consistently expose the bare carbon fiber at the distal portion 720 beyond the parylene-coated proximal portion 718 which remains protected inside the ice 750.

[0097] In some examples, multiple parylene-coated carbon fiber-tungsten wire assemblies 730 can be placed on the plate 760 and flame etched together or in a batch as the flame torch 740 moves across the distal portions 720 in a controlled manner.

[0098] After the flame etching, the ice 750 is allowed to thaw. In some examples, the distal portion 720 of the carbon fiber may be further trimmed (e.g., using a razor blade, or the like) to a desired length or if necessary, e.g., based on the background current measurements and / or impedance testing, as described further below.

[0099] The cryogenic flame etching process described herein can be more advantageous than conventional water-based etching process. In traditional water-based etching, a parylene- coated carbon fiber-tungsten wire assembly is substantially immersed in water, with only a distal portion of the carbon fiber extending above the water for flame etching. However, long probes, like the carbon fiber-tungsten wire assemblies disclosed here, have a tendency to collapse under the combined forces of water movement, surface tension, and external air drafts. In contrast, the cryogenic flame etching can provide a more controlled environment where the assemblies are held securely in place by the ice. This stabilizes the assemblies and8123-112336-02 eliminates the destabilizing effects of air drafts and water movement, ensuring precise flame etching of the distal portions without causing damage to the longer, more fragile probes.

[0100] In certain examples, an improved water-based etching process, in which the water is thermally insulated, can also be used to etch the distal portions of carbon fibers, especially if there is not a significant draft or air movement, or the length of the parylene-coated carbon fiber-tungsten wire assemblies are relatively short. Specifically, the parylene-coated carbon fiber-tungsten wire assembly can be substantially immersed in thermally controlled, roomtemperature water, while only the distal end of the carbon fiber is exposed for flame etching. The thermal insulation of the water — achieved, for example, through a temperature control mechanism — helps prevent excessive heat transfer through thermal conduction, protecting the parylene-coated carbon fibers from overheating. Without this thermal insulation, excessive heat could damage an area between the etched and coated portions of the carbon fiber, potentially compromising the functionality of the etched carbon fiber tip.

[0101] In some examples, after etching the distal portion of the carbon fiber, each carbon fiber-tungsten wire assembly 730 can be tested in vitro to ensure proper functionality. The testing can be performed in a beaker containing 0.9% sodium chloride (saline) solution, which allows for the evaluation of background current and noise levels before the assembly 730 is connected to a flexible printed circuit board (PCB) for FSCV and / or impedance testing. In some examples, multiple assemblies 730 can be connected to the PCB for simultaneous testing. To minimize electromagnetic interference during recordings, the testing setup can be placed inside a Faraday cage. This in vitro testing process can help detecting any structural defects in the carbon fibers (e.g., detecting perforations in the parylene insulated parts of the carbon fibers, etc.), and ensure that both the background current and noise level fall within the desired range. For instance, for dopamine detection, the electrode can be deemed satisfactory if the current noise is below a predefined threshold (e.g., less than 0.05 nA), and the background current falls within a predefined range (e.g., 800-1000 nA). If no structural defects are detected (indicated by low noise and absence of artifacts) but the current exceeds the acceptable range, the exposed carbon fiber tip can be trimmed and retested. For electrophysiological recordings, impedance measurements (e.g., via electrochemical impedance spectroscopy) can also be used to assess the electrode. In some examples, the electrode length can be limited to 100 microns or less to optimize singlecell recordings of electrophysiological signals. In some examples, surface modifications, such as PEDOT coatings, can be applied to increase surface roughness and adjust the exposed carbon fiber surface area as needed.8123-112336-02

[0102] After passing the in vitro test, the carbon fiber-tungsten wire assemblies or CFETs can be used to assemble neural probes. Specifically, two or more successfully tested CFETs can be threaded through a tubular body, such as a fused silica tube.

[0103] FIG. 8A illustrating threading a pair of CFETs 810 into a fused silica tube 802 to assemble a neural probe 800. Each CFET 810 has a carbon fiber 814 connected to a threading wire, such as a tungsten wire 804. The carbon fiber 814 has a parylene-coated proximal portion 818 and an exposed distal portion 820 (i.e., the electrode), and the tungsten wire 804 can also be parylene-coated, as described above. In the depicted example, the tube 802 has an inner diameter of about 101 microns and an outer diameter of about 165 microns. In other examples, the tube’s diameter can be different to accommodate different numbers of CFETs extending therethrough. The tube 802 can be cut to a predefined length (e.g., about 9 centimeters) with a tapered distal end portion 806. The tube 802 can be placed on a flat surface of an assembling platform 830, partially immersed in a puddle of IPA 822, which helps guide the threading process. After the threading process, the IPA 822 is allowed to evaporate.

[0104] The threading process begins by inserting the tungsten wires 804 (i.e., the proximal ends of the CFETs 810) through the tapered distal end portion 806 and into the inner lumen of the tube 802. The pair of CFETs 810 can be pushed through the fused silica tube 802 until a short proximal end portion (e.g., about 0.2 to 5 millimeters long) of each carbon fiber 814 is inside the tube 802, and a short proximal end portion (e.g., about 0.5 to 2 centimeters long) of each tungsten wires 804 extends out of a proximal end 808 of the tube 802, as shown in FIG. 8B.

[0105] The threading process can also leave a majority length of each carbon fiber 814 outside the tube 802. As described above, the axial length of the carbon fibers 814 extending outside the tube 802 can vary (e.g., between 1 and 15 millimeters) depending on desired usage of the corresponding electrodes. Additionally, the pitch, which defines the axial separation between the tips of the two carbon fibers 814, can be adjusted to a desired length (e.g., between 10 and 500 microns).

[0106] After threading the pair of CFETs 810 through the tube 802 and adjusting their axial positions, they can be permanently secured in place, e.g., using structural epoxy 816 applied to both ends of the tube 802, as illustrated in FIG. 8B.

[0107] In some examples, a heat shrink tube 826 can be cut to size (e.g., about 1 centimeter long) to reinforce about the proximal end portions of the two tungsten wires 804 extending out of the proximal end 808 of the tube 802, as shown in FIG. 8C. The heat shrink tube 8268123-112336-02 can be slid over the proximal end portions of the two tungsten wires 804 and allowed to shrink, firmly wrapping the tungsten wires 804 and the tube 802, for example, by gently applying heat with a soldering iron (e.g., at a temperature of about 180°C or less). In some examples, the most proximal or terminal ends of the tungsten wires 804 can be etched (e.g., using a flame torch) to remove the parylene coating, after which they can be connected to conductive wires 812. In some examples, the wires 812 can be connected to a PCB for further FSCV and / or impedance testing to ensure the two CFETs 810 remain functional and to record their background current and noise levels. Finally, the wires 812 can be connected to respective head stages so that the probe 800 is ready for in vivo testing or applications.

[0108] In any examples disclosed herein, the fabricated neural probes are suitable for both acute and chronic implantation. As used herein, “acute” implantation refers to short-term use ranging from minutes to hours, typically within a single experimental session lasting within one day. “Chronic” implantation refers to long-term use over extended periods, such as spanning multiple days, weeks, months, or years. For both acute and chronic applications, it is important that the neural probes maintain stable performance throughout the intended duration of use to ensure accurate and reliable signal acquisition. Performance degradation may be indicated by increased recording noise, structural failure such as probe breakage, and / or biofouling that impairs signal fidelity. In some examples, predefined thresholds for signal noise and / or impedance may be used to detect such degradation. The structural design and fabrication processes disclosed herein are configured to support stable performance of the neural probes across both acute and chronic implantation durations.Example Integration with Auxiliary Devices

[0109] In some embodiments, the disclosed neural probes may be temporarily or permanently adhered to another device in order to increase functionality and / or improve insertion yield. For example, the neural probe disclosed herein can be coupled to an insertion shuttle, guide, or stiffener to provide additional mechanical support during penetration of dense meningeal tissue or deeper brain regions, thereby reducing the likelihood of buckling or breakage of the CFETs. In other examples, the disclosed neural probe may be integrated with another microelectrode or electrode array to enable multimodal or multi-site recordings within a shared implantation trajectory. Such configurations enable the neural probes to achieve enhanced spatial targeting, support combined electrophysiological and neurochemical measurements, and improve insertion reliability, all while preserving the micro-invasive profile and minimal tissue disruption afforded by the carbon fiber tips.8123-112336-02Example Computing Systems

[0110] FIG. 9 depicts an example of a suitable computing system 900 which can be integrated with or in communication with the interface platform 300 of FIG. 3. The computing system 900 is not intended to suggest any limitation as to scope of use or functionality of the present disclosure, as the innovations can be implemented in diverse computing systems.

[0111] With reference to FIG. 9, the computing system 900 includes one or more processing units 910, 915 and memory 920, 925. In FIG. 9, this basic configuration 930 is included within a dashed line. The processing units 910, 915 execute computer-executable instructions, such as for implementing the features described in the examples herein. A processing unit can be a general-purpose central processing unit (CPU), processor in an application-specific integrated circuit (ASIC), or any other type of processor. In a multiprocessing system, multiple processing units execute computer-executable instructions to increase processing power. For example, FIG. 9 shows a central processing unit 910 as well as a graphics processing unit or co-processing unit 915. The tangible memory 920, 925 can be volatile memory (e.g., registers, cache, RAM), non-volatile memory (e.g., ROM, EEPROM, flash memory, etc.), or some combination of the two, accessible by the processing unit(s) 910, 915. The memory 920, 925 stores software 980 controlling operations of the head stages (e.g., for measuring signals from and / or delivering electrical pulses to neural probes), in the form of computer-executable instructions suitable for execution by the processing unit(s) 910, 915.

[0112] A computing system 900 can have additional features. For example, the computing system 900 includes storage 940, one or more input devices 950, one or more output devices 960, and one or more communication connections 970, including input devices, output devices, and communication connections for interacting with a user. An interconnection mechanism (not shown) such as a bus, controller, or network interconnects the components of the computing system 900. Typically, operating system software (not shown) provides an operating environment for other software executing in the computing system 900, and coordinates activities of the components of the computing system 900.

[0113] The tangible storage 940 can be removable or non-removable, and includes magnetic disks, magnetic tapes or cassettes, CD-ROMs, DVDs, or any other medium which can be used to store information in a non-transitory way and which can be accessed within the computing system 900. The storage 940 stores instructions for the software implementing one or more innovations described herein.8123-112336-02

[0114] The input device(s) 950 can be an input device such as a keyboard, mouse, pen, or trackball, a voice input device, a scanning device, touch device (e.g., touchpad, display, or the like) or another device that provides input to the computing system 900. The output device(s) 960 can be a display, printer, speaker, CD-writer, or another device that provides output from the computing system 900.

[0115] The communication connection(s) 970 enable communication over a communication medium to another computing entity. The communication medium conveys information such as computer-executable instructions, audio or video input or output, or other data in a modulated data signal. A modulated data signal is a signal that has one or more of its characteristics set or changed in such a manner as to encode information in the signal. By way of example, and not limitation, communication media can use an electrical, optical, RF, or other carrier.

[0116] The innovations can be described in the context of computer-executable instructions, such as those included in program modules, being executed in a computing system on a target real or virtual processor (e.g., which is ultimately executed on one or more hardware processors). Generally, program modules or components include routines, programs, libraries, objects, classes, components, data structures, etc. that perform particular tasks or implement particular abstract data types. The functionality of the program modules can be combined or split between program modules as desired in various examples. Computerexecutable instructions for program modules can be executed within a local or distributed computing system.

[0117] For the sake of presentation, the detailed description uses terms like “determine” and “use” to describe computer operations in a computing system. These terms are high-level descriptions for operations performed by a computer and should not be confused with acts performed by a human being. The actual computer operations corresponding to these terms vary depending on implementation.Example Clauses

[0118] In view of the above-described implementations of the disclosed subject matter, this application discloses the additional clauses enumerated below.

[0119] Clause 1. A probe for insertion into brain tissue, the probe comprising: a tubular body having an inner lumen; and at least two carbon fiber electrode threads (CFETs) extending through the inner lumen of the tubular body, wherein each CFET comprises a carbon fiber having a proximal portion and a distal portion, wherein the proximal portion of the carbon fiber is coated with a polymer, wherein the distal portion of the carbon fiber is exposed to8123-112336-02 allow direct contact with the brain tissue, wherein the carbon fiber of each CFET has an aspect ratio between 100 and 1500.

[0120] Clause 2. The probe of clause 1 , wherein the tubular body comprises fused silica.

[0121] Clause 3. The probe of any one of clauses 1-2, wherein the inner lumen of the tubular body has a diameter between 80 and 120 microns.

[0122] Clause 4. The probe of any one of clauses 1-3, wherein the tubular body has an axial length between 8 and 80 centimeters, wherein the carbon fiber of each CFET extends out of a distal end portion of the tubular body by a length between 1 and 20 millimeters.

[0123] Clause 5. The probe of clause 4, wherein the distal end portion of the tubular body tapers radially inwardly in a distal direction.

[0124] Clause 6. The probe of any one of clauses 1-5, wherein the polymer comprises parylene.

[0125] Clause 7. The probe of any one of clauses 1-6, wherein the distal portion of the carbon fiber has an outer diameter between 4 and 8 microns, wherein the proximal portion of the carbon fiber has an outer diameter that is between 1 and 3 microns larger than the outer diameter of the distal portion.

[0126] Clause 8. The probe of any one of clauses 1-7, wherein the distal portion of the carbon fiber of one of the at least two CFETs has an axial length between 5 and 300 microns, wherein the distal portion of the carbon fiber of another one of the at least two CFETs has an axial length between 100 and 500 microns.

[0127] Clause 9. The probe of any one of clauses 1-8, wherein distal ends of the carbon fibers of the at least two CFETs are axially offset from one another by a distance between 10 microns and 1 millimeter.

[0128] Clause 10. The probe of any one of clauses 1-9, wherein a proximal end of the carbon fiber of each CFET is connected to a tungsten wire, wherein a body portion of the tungsten wire is coated with the polymer and situated within the inner lumen, wherein a proximal end portion of the tungsten wire extends out of a proximal end of the tubular body.

[0129] Clause 11. The probe of any one of clauses 1-10, wherein the at least two CFETs comprises a first CFET and a second CFET, wherein the first CFET is electrically connected to a first circuitry configured to measure electrophysiological signals of the brain tissue surrounding the distal portion of the carbon fiber of the first CFET, wherein the second CFET is electrically connected to a second circuitry configured to measure neurochemical signals of the brain tissue surrounding the distal portion of the carbon fiber of the second CFET.8123-112336-02

[0130] Clause 12. The probe of any one of clauses 1-10, wherein the at least two CFETs comprises a first CFET and a second CFET, wherein the first CFET is electrically connected to a first circuitry configured to measure electrophysiological or neurochemical signals of the brain tissue surrounding the distal portion of the carbon fiber of the first CFET, wherein the second CFET is electrically connected to a second circuitry configured to deliver electrical pulses to the brain tissue surrounding the distal portion of the carbon fiber of the second CFET.

[0131] Clause 13. A method for fabricating a probe for insertion into brain tissue, the method comprising: forming at least two carbon fiber electrode threads (CFETs), wherein each CFET comprises a carbon fiber having an aspect ratio between 100 and 1500; threading the at least two CFETs through an inner lumen of a tubular body; connecting one of the at least two CFETs to a first circuitry configured to measure electrophysiological signals of the brain tissue; and connecting another one of the at least two CFETs to a second circuitry configured to measure neurochemical signals of the brain tissue.

[0132] Clause 14. The method of clause 13, wherein forming the at least two CFETs comprises forming two carbon fiber-tungsten wire assemblies and coating the two carbon fiber-tungsten wire assemblies with a polymer, wherein forming the two carbon fiber- tungsten wire assemblies comprises connecting two carbon fibers to two tungsten wires, respectively.

[0133] Clause 15. The method of clause 14, wherein the coating comprises placing the two carbon fiber-tungsten wire assemblies in a vacuum chamber and keeping the two carbon fiber-tungsten wire assemblies separate from one another, and evaporating a liquid adhesion promoter within the vacuum chamber.

[0134] Clause 16. The method of any one of clauses 14-15, wherein forming the at least two CFETs further comprises etching distal portions of the two carbon fiber-tungsten wire assemblies.

[0135] Clause 17. The method of clause 16, wherein the etching comprises heating the distal portions of the two carbon fiber-tungsten wire assemblies while freezing at least body portions of the two carbon fiber-tungsten wire assemblies in ice.

[0136] Clause 18. The method of any one of clauses 13-17, wherein the threading comprises inserting the at least two CFETs into the inner lumen from a tapered distal end portion of the tubular body, and extending proximal end portions of the at least two CFETs out of a proximal end of the tubular body.8123-112336-02

[0137] Clause 19. A probe for insertion into brain tissue, the probe comprising: a tubular body having an inner lumen; and a plurality of carbon fiber electrode threads (CFETs) extending through the inner lumen of the tubular body, wherein each CFET comprises a carbon fiber having a proximal portion and a distal portion, wherein the proximal portion of the carbon fiber is coated with a polymer, wherein the distal portion of the carbon fiber is exposed to allow direct contact with the brain tissue, wherein the plurality of CFETs comprises a first CFET and a second CFET, wherein the distal portion of the carbon fiber of the second CFET has a larger surface area than the distal portion of the carbon fiber of the first CFET, wherein the first CFET is electrically connected to a first circuitry configured to measure electrophysiological signals of the brain tissue surrounding the distal portion of the carbon fiber of the first CFET, wherein the second CFET is electrically connected to a second circuitry configured to measure neurochemical signals of the brain tissue surrounding the distal portion of the carbon fiber of the second CFET.

[0138] Clause 20. The probe of clause 19, wherein the carbon fiber of each CFET has an aspect ratio between 100 and 1500, wherein the inner lumen of the tubular body has a diameter between 80 and 120 microns.

[0139] The technologies from any clause can be combined with the technologies described in any one or more of the other clauses. In view of the many possible examples to which the principles of the disclosed technology can be applied, it should be recognized that the illustrated embodiments are examples of the disclosed technology and should not be taken as a limitation on the scope of the disclosed technology. Rather, the scope of the claimed subject matter is defined by the following claims and their equivalents.

Claims

8123-112336-02We claim:

1. A probe for insertion into brain tissue, the probe comprising: a tubular body having an inner lumen; and at least two carbon fiber electrode threads (CFETs) extending through the inner lumen of the tubular body, wherein each CFET comprises a carbon fiber having a proximal portion and a distal portion, wherein the proximal portion of the carbon fiber is coated with a polymer, wherein the distal portion of the carbon fiber is exposed to allow direct contact with the brain tissue, wherein the carbon fiber of each CFET has an aspect ratio between 100 and 1500.

2. The probe of claim 1 , wherein the tubular body comprises fused silica.

3. The probe of claim 1, wherein the inner lumen of the tubular body has a diameter between 80 and 120 microns.

4. The probe of claim 1, wherein the tubular body has an axial length between 8 and 80 centimeters, wherein the carbon fiber of each CFET extends out of a distal end portion of the tubular body by a length between 1 and 20 millimeters.

5. The probe of claim 4, wherein the distal end portion of the tubular body tapers radially inwardly in a distal direction.

6. The probe of claim 1, wherein the polymer comprises parylene.

7. The probe of any claim 1, wherein the distal portion of the carbon fiber has an outer diameter between 4 and 8 microns, wherein the proximal portion of the carbon fiber has an outer diameter that is between 1 and 3 microns larger than the outer diameter of the distal portion.

8. The probe of claim 1, wherein the distal portion of the carbon fiber of one of the at least two CFETs has an axial length between 5 and 300 microns, wherein the distal portion of the carbon fiber of the other one of the at least two CFETs has an axial length between 100 and 500 microns.8123-112336-029. The probe of claim 1, wherein distal ends of the carbon fibers of the at least two CFETs are axially offset from one another by a distance between 10 microns and 1 millimeter.

10. The probe of claim 1, wherein a proximal end of the carbon fiber of each CFET is connected to a tungsten wire, wherein a body portion of the tungsten wire is coated with the polymer and situated within the inner lumen, wherein a proximal end portion of the tungsten wire extends out of a proximal end of the tubular body.

11. The probe of claim 1, wherein the at least two CFETs comprises a first CFET and a second CFET, wherein the first CFET is electrically connected to a first circuitry configured to measure electrophysiological signals of the brain tissue surrounding the distal portion of the carbon fiber of the first CFET, wherein the second CFET is electrically connected to a second circuitry configured to measure neurochemical signals of the brain tissue surrounding the distal portion of the carbon fiber of the second CFET.

12. The probe of claim 1, wherein the at least two CFETs comprises a first CFET and a second CFET, wherein the first CFET is electrically connected to a first circuitry configured to measure electrophysiological or neurochemical signals of the brain tissue surrounding the distal portion of the carbon fiber of the first CFET, wherein the second CFET is electrically connected to a second circuitry configured to deliver electrical pulses to the brain tissue surrounding the distal portion of the carbon fiber of the second CFET.

13. A method for fabricating a probe for insertion into brain tissue, the method comprising: forming at least two carbon fiber electrode threads (CFETs), wherein each CFET comprises a carbon fiber having an aspect ratio between 100 and 1500; threading the at least two CFETs through an inner lumen of a tubular body; connecting one of the at least two CFETs to a first circuitry configured to measure electrophysiological signals of the brain tissue; and connecting another one of the at least two CFETs to a second circuitry configured to measure neurochemical signals of the brain tissue.8123-112336-0214. The method of claim 13, wherein forming the at least two CFETs comprises forming two carbon fiber-tungsten wire assemblies and coating the two carbon fiber-tungsten wire assemblies with a polymer, wherein forming the two carbon fiber-tungsten wire assemblies comprises connecting two carbon fibers to two tungsten wires, respectively.

15. The method of claim 14, wherein the coating comprises placing the two carbon fiber- tungsten wire assemblies in a vacuum chamber and keeping the two carbon fiber-tungsten wire assemblies separate from one another, and evaporating a liquid adhesion promoter within the vacuum chamber.

16. The method of claim 14, wherein forming the at least two CFETs further comprises etching distal portions of the two carbon fiber-tungsten wire assemblies.

17. The method of claim 16, wherein the etching comprises heating the distal portions of the two carbon fiber-tungsten wire assemblies while freezing at least body portions of the two carbon fiber-tungsten wire assemblies in ice.

18. The method of claim 13, wherein the threading comprises inserting the at least two CFETs into the inner lumen from a tapered distal end portion of the tubular body, and extending proximal end portions of the at least two CFETs out of a proximal end of the tubular body.

19. A probe for insertion into brain tissue, the probe comprising: a tubular body having an inner lumen; and a plurality of carbon fiber electrode threads (CFETs) extending through the inner lumen of the tubular body, wherein each CFET comprises a carbon fiber having a proximal portion and a distal portion, wherein the proximal portion of the carbon fiber is coated with a polymer, wherein the distal portion of the carbon fiber is exposed to allow direct contact with the brain tissue, wherein the plurality of CFETs comprises a first CFET and a second CFET, wherein the distal portion of the carbon fiber of the second CFET has a larger surface area than the distal portion of the carbon fiber of the first CFET, wherein the first CFET is electrically connected to a first circuitry configured to measure electrophysiological signals of the brain tissue surrounding the distal portion of the8123-112336-02 carbon fiber of the first CFET, wherein the second CFET is electrically connected to a second circuitry configured to measure neurochemical signals of the brain tissue surrounding the distal portion of the carbon fiber of the second CFET.

20. The probe of claim 19, wherein the carbon fiber of each CFET has an aspect ratio between 100 and 1500, wherein the inner lumen of the tubular body has a diameter between 80 and 120 microns.

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